Osmotic system with instant drug availability

ABSTRACT

An osmotic device is disclosed for delivering a beneficial agent. The device comprises a wall surrounding a compartment containing an agent, a passageway in the wall connecting the exterior of the device with the compartment, and (a) an agent in the wall or (b) an agent carried on the wall in the wall. The device delivers the agent from the compartment and the wall.

FIELD OF THE INVENTION

This invention pertains to a therapeutic system that is a controlleddosage form. The therapeutic osmotic system provides a preprogrammed,unattended delivery of a beneficial drug, that is initially delivered inan increased therapeutically effective amount, followed by delivery ofdrug at a controlled rate, and for a time period, established to meet aspecific therapeutic need. The osmotic system is manufactured in theform of an osmotic device for delivering drug to a selected drugreceptor site.

BACKGROUND OF THE INVENTION

Osmotic therapeutic systems manufactured in the form of osmotic devicesfor the precision administration of drugs with control of deliverypatterns, and with extended operational delivery times are known in U.S.Pat. Nos. 3,845,770 and 3,916,899 both issued to inventors FelixTheeuwes and Takeru Higuchi. The osmotic systems disclosed in thesepioneer patents are made of a semipermeable wall that surrounds areservoir containing drug. The wall is permeable to the passage of anexternal fluid, impermeable to the passage of drug, and it has apassageway through the semipermeable wall for delivering drug from theosmotic system. These systems are extraordinarily effective fordelivering a drug that is soluble in the fluid, and also for deliveringa drug that has limited solubility in the fluid and is mixed with anosmotically effective compound that is soluble in the fluid and exhibitsan osmotic pressure gradient across the wall against the fluid. Theosmotic systems release drug by fluid being imbibed through thesemipermeable wall into the reservoir at a rate determined by thepermeability of the semipermeable wall and the osmotic pressure gradientacross the wall producing a solution of soluble drug, or a solution ofsoluble compound containing drug, which solution in either operation isdelivered at a controlled rate over a prolonged period of time.

An unobvious and unexpected advance was made in osmotic systems bypatentees Felix Theeuwes and Atul D. Ayer as disclosed in U.S. Pat. Nos.4,008,719; 4,014,334; 4,058,122; 4,116,241; 4,160,452; and 4,256,108. Inthese patents, the patentees provided osmotic systems comprising alaminated wall formed of two laminae, a semipermeable lamina and amicroporous lamina, that act in cooperation to provide improvedcontrolled delivery of drug over a prolonged period of time. The twolaminae maintain their physical and chemical integrity during thecontrolled dispensing of drug, and the laminate allows a wider controlover the rate at which drug is delivered to a drug receptor site over aprolonged period of time.

While the above osmotic systems comprising a single layer semipermeablewall, and the osmotic systems comprising the laminated wall consistingof a semipermeable lamina and a microporous lamina represent outstandingand pioneering advancements in the osmotic delivery art, and while theyare useful for dispensing innumerable drugs to the environment of use,it has now been discovered that these osmotic systems can be improvedfurther to enhance the drug delivery kinetics and the usefulness of theosmotic systems. That is, it has now been discovered unexpectedly thatosmotic systems can be provided that initially deliver a bio-affectingdrug in an increased amount followed by a substantially constant amountat a controlled rate over time; thereby, making drug available instantlyto a drug receptor by substantially eliminating the start-up drugdelivery time frequently required to deliver some drugs by osmoticsystems. The therapeutic osmotic systems made available by thisinvention embodying the unique initial drug delivery followed bycontrolled and constant prolonged delivery, thereby function accordingto a pre-selected built-in optimal program of drug presentation.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide an improved osmotic delivery systemfor the controlled delivery of drug initially in an increased amountfollowed by a constant amount to a drug receptor site over a prolongedperiod of time.

Another object of the invention is to provide an osmotic systemcomprising a semipermeable wall containing drug that is available forinstant delivery in an increased amount thereby providing an osmoticsystem that delivers drug immediately when in operation in theenvironment of use.

Another object of the invention is to provide an osmotic systemcomprising a laminated wall comprising an interior lamina and anexterior lamina, which latter lamina contains a drug that is availablefor immediate delivery as a burst of drug for substantially eliminatingthe start-up time sometimes required for certain drugs.

Another object of the invention is to provide an osmotic systemmanufactured in the form of an osmotic device that comprises anoutermost lamina consisting essentially of a composition of drug and areleasable binder that delivers drug immediately for increasing theperiod of time drug is available for performing its beneficial effects.

Yet still another object of the invention is to provide an osmoticsystem adapted for administering drug to an animal from adrug-containing outermost lamina for delivering an initial drug-pulsewhich acts in cooperation with the osmotic system that follows with drugdelivery at a rate controlled by the osmotic system.

Still yet another object of the invention is to provide a method forforming a microporous lamina in a biological environment for increasingthe volume of fluid available for imbibition by an osmotic device, whileconcomitantly increasing the amount of drug available to the biologicalenvironment.

Still yet another object of the invention is to provide a method forincreasing the amount of drug available for producing a beneficialeffect by making available an osmotic device that delivers an increasedamount of drug for diminishing the incidence of drug loss attributed tothe unwanted metabolic effects of the gastrointestional tract or theunwanted metabolic effects of drug passage through the liver.

Yet still another object of the invention is to provide (1) a laminatecomprising a semipermeable lamina in laminar arrangement with a laminaformed of a water-soluble material containing drug; (2) a laminatecomprising a semipermeable lamina containing drug in laminar arrangementwith a lamina formed of a water-soluble material containing drug; (3) alaminate comprising a semipermeable lamina in laminar arrangement with amicroporous lamina which latter lamina is in laminar arrangement with alamina formed of a water-soluble polymer containing drug; and (4) alaminate comprising a semipermeable lamina in laminar arrangement with amicroporous lamina containing drug, which microporous lamina is inlaminar arrangement with a lamina formed of a water-soluble materialcontaining drug, and wherein laminates 1 through 4 are useful formanufacturing osmotic systems.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the art from the following detailedspecification, taken in conjunction with the drawings and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1 is an isometric view of an osmotic device designed for orallyadministering a beneficial agent to the gastrointestinal environment;

FIG. 2 is an opened view of the osmotic device of FIG. 1 with FIG. 2illustrating the structure of the osmotic device;

FIG. 3 is an opened view of the osmotic device depicting thesemipermeable wall of the device bearing an exterior fluid-solublelamina containing drug;

FIG. 4 is an osmotic device with a section removed for depicting theinternal structure and the laminated wall comprising an outer laminahousing releasable drug;

FIG. 5 is an osmotic device with a section removed for depicting thereservoir of the osmotic device and its laminated wall coated with awater-soluble lamina containing drug;

FIG. 6 is an osmotic device in opened section depicting the structure ofthe device including a microporous lamina containing drug and anoutermost water-soluble lamina containing drug;

FIG. 7 shows an osmotic device designed for delivering a beneficial druginto a body passageway, such as the ano-rectal and vaginal passageways;

FIG. 8 shows the osmotic therapeutic system of FIG. 7, with its wallpartially broken away for elucidating the structural details thereof;

FIG. 9 is a bar graph that depicts the release rate profile for a drugfrom a semipermeable wall of an osmotic device;

FIG. 10 depicts the release rate profile for an osmotic device madeaccording to the invention;

FIG. 11 illustrates a laminate structure comprising a semipermeablelamina laminated to a lamina containing drug for quick release;

FIG. 12 depicts a laminate comprising a semipermeable lamina containingdrug in laminar arrangement with water soluble lamina containing drug;

FIG. 13 depicts the release of drug from an osmotic device over aprolonged period of time;

FIG. 14 depicts the cumulative amount of drug released by the osmoticdevice of FIG. 13;

FIG. 15 depicts a pulsed release of drug accompanied by prolongedrelease of drug from an osmotic device;

FIG. 16 depicts the cumulative amount of drug released from the osmoticdevice of FIG. 15 over time;

FIG. 17 depicts the release profile for another osmotic device made inthe form of an osmotic tablet;

FIG. 18 depicts a laminate comprising a microporous lamina containingdrug laminated to a semipermeable lamina;

FIG. 19 depicts the release rate profile for an osmotic devicecomprising a laminate formed of three lamina, a semipermeable lamina, amicroporous lamina containing drug, and a water-soluble laminacontaining drug;

FIG. 20 depicts a laminate comprising a semipermeable lamina, amicroporous lamina containing drug, and a water soluble laminacontaining drug;

FIG. 21 depicts a laminate comprising a semipermeable lamina, amicroporous lamina, and a water soluble lamina containing drug.

In the drawings and the specification, like parts in related figures areidentified by like parts. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are examples of variousosmotic systems provided by the invention, and which examples are not tobe construed as limiting, one embodiment of an osmotic system is seen inFIG. 1 as indicated by the numeral 10. In FIG. 1, osmotic system 10 ismanufactured as an oral, osmotic device comprising a body 11 that can beshaped, sized, adapted and structured for easy placement and prolongedretention in a biological environment of use for the controlled deliveryof a beneficial agent thereto. Osmotic device 10 comprises wall 12 witha passageway 13 through wall 12 for connecting the inside of osmoticdevice 10 with the exterior of osmotic device 10.

In FIG. 2, osmotic device 10 is seen in opened-section. In FIG. 2,device 10 comprises body 11 having wall 12 that surrounds and forms acompartment 14. Wall 12 is formed of a semipermeable polymer that ispermeable to the passage of an exterior fluid and substantiallyimpermeable to the passage of drugs and osmotically effective agents.Wall 12 contains a drug 15, represented by dots, that is releasedinstantly, or in a short time, from wall 12 when device 10 is inoperation in a biological environment of use. Wall 12 of device 10 issubstantially inert, it maintains its physical and chemical integrityduring the dispensing of an active beneficial drug, and it is formed ofa semipermeable material that is nontoxic to a host. A passageway 13 inwall 12 connects compartment 14 with the exterior of device 10.Compartment 14 houses beneficial drug 16 that is soluble in an externalfluid 17, represented by dashes, imbibed through semipermeable wall 12into compartment 14, and it exhibits an osmotic pressure gradient acrosswall 12 against an external fluid. Compartment 14 optionally contains anosmotically effective solute 18, represented by wavy lines, that issoluble in the fluid and exhibits an osmotic pressure gradient acrosswall 12.

In operation, osmotic device 10 of FIGS. 1 and 2, manufactured in theform of an osmotic tablet, on entering a biological fluid environment ofuse, such as the gastrointestional tract of a warm-blooded animal,initially delivers drug 15 from wall 12 to the environment of use. Thisinitial delivery of drug 15 makes drug available immediately to the hostby eliminating the start-up time needed before drug is delivered bydevice 10. The delivery of drug 15, usually over a period of an hour ormore, is effected independent of delivery of drug 16 by device 10.Device 10 may deliver drug 16 during the period of time drug 15 isdelivered, or device 10 may deliver drug 16 after delivering of drug 15.Drug 15 and drug 16 may in an optional embodiment be the same drug ordifferent drug.

Osmotic device 10 releases drug 16 contained in reservoir 14 by fluidbeing imbibed into compartment 14 in a tendency towards osmoticequilibrium at a rate controlled by the permeability of semipermeablewall 12 and the osmotic pressure gradient across semipermeable wall 12to continuously dissolve agent 16, which is osmotically pumped fromcompartment 14 through passageway 13 at a controlled and continuous rateover a prolonged period of time. Osmotic device 10, also releases agent16 that has limited solubility in fluid 17 and is mixed with anosmotically effective compound 18 by fluid 17 being imbibed throughsemipermeable wall 12 into reservoir compartment 14, in a tendencytowards osmotic equilibrium at a rate controlled by the permeability ofwall 12 and the osmotic pressure gradient across wall 12, tocontinuously dissolve osmotically effective compound 18 and form asolution thereof containing drug 16 that is released from device 10through passageway 13 at a controlled and continuous rate over aprolonged period of time.

FIG. 3 represents another therapeutic osmotic device manufacturedaccording to the invention for administering drug to a drug receptor. Inthe illustrated embodiment, osmotic device 10 is seen with a sectionremoved and it comprises body 11, semipermeable wall 12, passageway 13,and compartment 14 containing drug 16, imbibed fluid 17 and osmoticallyeffective compound 18. Device 10 of FIG. 3 comprises further a lamina 19coated onto the exterior surface of semipermeable wall 12. Lamina 19 isformed of an aqueous soluble material, an aqueous disintegratingmaterial, or the like, and it contains drug 20. Lamina 19 containingdrug 20 is provided for making available instantly drug 20. In operationwhen device 10 is in a fluid environment, lamina 19 dissolves orundergoes dissolution and concurrently delivers drug 20 to a drugreceptor. Lamina 19 containing drug 20 by providing immediate drugdelivery, overcomes the time required for drug 16 to be delivered fromdevice 10. A start-up time is needed frequently for imbibing fluidthrough semipermeable wall 12, and for hydrating with imbibed fluid 17 adrug that lost its water of hydration during drying or solventevaporation processes used for manufacturing device 10. Lamina 19containing drug 20 operates independent of device 10 which device 10delivers drug 16 as described for FIG. 2. While FIG. 3 depicts lamina 19containing drug 20, and FIG. 2 depicts semipermeable wall 12 containingdrug 15, it is understood the invention embraces an osmotic device 10comprising a semipermeable wall 12 containing drug 15 laminated withlamina 19 containing drug 20.

FIG. 4 illustrates in opened view an osmotic system 10 made in the formof an oral, osmotic device comprising body 11 and a laminated wall 21that surrounds reservoir compartment 14. Laminated wall 21 has a portalor passageway 13 that communicates with compartment 14 and the exteriorof osmotic device 10. Compartment 14 contains beneficial drug 16 that issoluble in external fluid 17 imbibed through laminated wall 21, and drug16 exhibits an osmotic pressure gradient across laminated wall 12against an external fluid. Optionally, compartment 14 contains drug 16having limited solubility in the fluid and it is present in compartment14 with an osmotically effective solute 18. Solute 18 is soluble in thefluid and it exhibits an osmotic pressure gradient across laminated wall12.

Laminated wall 21 comprises a semipermeable lamina 22 that is theinterior lamina facing compartment 14, and a microporous lamina 23,distant from compartment 14 and in the osmotic device of FIG. 4,microporous lamina 23 is the exterior lamina facing the environment ofuse. Semipermeable lamina 22 is permeable to the passage of an externalfluid and it is substantially impermeable to the passage of drug andother agents. Semipermeable lamina 22 is formed of a material thatmaintains its physical and chemical integrity in the presence of drug,agent and fluid, it is substantially non-erodible and inert, and it canbe made from very thin to thick while simultaneously controlling thepermeability to fluid for imbibition by osmotic device 10. Microporouslamina 23 in one embodiment functions as a support or rigid structurefor semipermeable lamina 22, particularly when the latter lamina 22 isthin. Microporous lamina 23 can have preformed micropores, ormicroporous lamina 23 can contain a microporous pore former, describedhereinafter. In this embodiment microporous lamina 23 is formed in situby exterior fluid wetting and dissolving the pore-former that leaves toform microporous lamina 23. Microporous lamina 23 is permeable to thepassage of fluid and the material forming microporous lamina 23, housingthe pore-former, maintains its physical and chemical integrity in theenvironment of use, and it is substantially non-erodible and inert inthe environment of use. Additionally, in osmotic device 10 of FIG. 4,microporous lamina 23 houses drug 24 that is available for rapid,initial drug delivery to a drug receptor. Drug 24 can serve as a solepore-former to form a microporous lamina in embodiment of this inventionwhen the amount of drug is in excess of 40% in lamina 23. Drug 24 cancooperate with a nondrug pore-former for forming a microporous lamina,in embodiments when the combined amount of drug and pore-former excessed25%, by weight. The delivery of drug 24 from microporous lamina 23 isadditional to delivery of drug 16 at a controlled and continuous rate byosmotic device 10.

FIG. 5 illustrates, in opened view, an osmotic device 10 that isstructurally similar to osmotic device 10 of FIG. 4. In FIG. 5, osmoticdevice 10 additionally comprises lamina 25 comprising drug 26. Lamina 25is coated onto the exterior surface of device 10. Lamina 25, theoutermost lamina, is formed of an aqueous soluble material, or amaterial soluble in, or disintegrated by the environment of use, such asthe acidic fluid of the stomach. Lamina 25 contains a water-soluble drug26, or a drug 26 that has limited solubility in the exterior fluids.Lamina 25 releases drug 26 by erosion, dissolution or the like. Lamina25 provides an initial burst or dosing of drug 26 for raising theblood-plasma level of drug up to a therapeutic level as quickly aspossible after the initial dosing of drug 26. The initial dosing of drug26 can be immediate total drug dosing, or it can be over a period of 15minutes to 75 minutes. The initial dosing of drug 26 diminishes the timedrug is unavailable to a host by supplying drug during the start-up timerequired for osmotic device 10 to deliver drug. The initial dosing ofdrug can be supplied in an increased amount also for lessening theeffects of in vivo metabolism. The initial dosing is effected withoutaffecting the release kinetics and the rate controlling properties ofosmotic device 10.

FIG. 6 illustrates, in opened view, an osmotic device 10 that is anembodiment of device 10 of FIGS. 4 and 5. In FIG. 6, device 10 comprisesan outermost lamina 25 containing drug 26 and microporous lamina 23containing drug 24. Lamina 25 containing drug 26 provides an immediatepulse or large burst of drug 26 followed by microporous lamina 23providing an increased amount of drug 24. Drug 24 and drug 26 can be thesame or different and they are administered for their therapeuticeffects.

FIGS. 7 and 8 represent another osmotic therapeutic system 10manufactured according to the invention for administering drug to a drugreceptor. In the illustrated embodiment, system 10 is designed forreleasing drug in the vagina or the ano-rectal passage, both not shown.System 10 has an elongated-shaped body 30 with a string 31 attachedthereto for removing system 10 from a body passageway. System 10comprises a portal 13 and it is formed with a laminated wall comprisingan exterior semipermeable lamina 32 and an interior microporous lamina33, both seen as dashed lines in FIG. 7, and in opened view in FIG. 8.Semipermeable lamina 32 contains drug 34 available for instant therapy.The amount of drug 34 in semipermeable lamina 32 is from 0.5 to 40% byweight, for maintaining the semipermeable properties of the lamina. Thelaminated wall surrounds compartment 35 containing drug 36. Osmoticdevice 10 operated as above described for FIGS. 1 through 6.

FIGS. 1 through 8 are illustrative of various osmotic devices 10 thatcan be made according to the invention, and it is to be understood thesedevices are not to be construed as limiting, as the devices can take awide variety of shapes, sizes and forms adapted for delivering agents todifferent environments of use. For example, the osmotic device includesbuccal, implant, topical, nose, artificial, gland, rectum, cervical,intrauterine, arterial, venous, ear, and the like biologicalenvironments. The devices can be adapted also for delivering an activeagent in streams, aquariums, fields, factories, reservoirs, laboratoryfacilities, hot houses, hospitals, veterinary clinics, nursing homes,chemical reactions, and other environments.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, it has now been foundthat osmotic devices can be manufactured with (1) a semipermeable wallcontaining drug, (2) a semipermeable wall containing drug and coatedwith a fluid soluble lamina containing drug, (3) a semipermeable wallcoated with a fluid soluble lamina containing drug, (4) a laminated wallcomprising a semipermeable lamina and a microporous lamina with drug inthe microporous lamina, (5) a laminated wall comprising a semipermeablelamina and a microporous lamina containing drug and coated with a fluidsoluble lamina containing drug, (6) a laminated wall comprising asemipermeable lamina and a microporous lamina coated with a fluidsoluble lamina containing drugs, (7) a microporous lamina and asemipermeable lamina containing drug, and the like.

The semipermeable wall is formed of a material that does not adverselyaffect the agent or drug, osmagent, an animal host, is permeable to thepassage of an external fluid such as water and biological fluids, and itis substantially impermeable to the passage of agents, osmagents, andthe like. The selectively semipermeable materials are non-erodible andthey are insoluble in fluids. Typical materials for forming wall 12 inone embodiment are cellulose esters, cellulose ethers and celluloseester-ethers. These cellulosic polymers have a degree of substitution,D.S., on the anhydroglucose unit from greater than 0 up to 3 inclusive.By degree of substitution is meant the average number of hydroxyl groupsoriginally present on the anhydroglucose unit comprising the cellulosepolymer that are replaced by a substituting group. Representativematerials include a member selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate, cellulose triacetate, mono, di andtricellulose alkanylates, mono, di and tricellulose aroylates, and thelike, Exemplary polymers include cellulose acetate having a D.S. up to 1and an acetyl content up to 21%; cellulose acetate having an acetylcontent of 32 to 39.8%; cellulose diacetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose triacetate having a D.S. of 2to 3 and an acetyl content of 35 to 44.8%; and the like. More specificcellulosic polymers include cellulose propionate having a D.S. of 1.8and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to5.4%; cellulose acetate-butyrate having a D.S. of 1.8, an acetyl contentof 13 to 15% and a butyryl content of 34 to 39%; cellulose acetatebutyrate having an acetyl content of 2 to 29%, a butyryl content of 17to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioclanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioclanoate, cellulose dipentale, and the like.

Additional semipermeable polymers include acetaldehyde dimethyl acetate,cellulose acetate ethyl carbamate, cellulose acetate phthalate for usein environments having a low ph, cellulose acetate methyl carbamate,cellulose acetate dimethyl aminoacetate, semipermeable polyamides,semipermeable polyurethanes, semipermeable sulfonated polystyrenes,cross-linked selectively semipermeable polymers formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; lightly cross-linked polystyrene derivatives;cross-linked poly(sodium styrene sulfonate), cross-linkedpoly(vinylbenzyltrimethyl ammonium chloride), semipermeable polymersexhibiting a fluid permeability of 10⁻⁵ to 10⁻¹ (cc.mil/cm².hr.atm)expressed as per atmosphere of hydrostatic or osmotic pressuredifference across the semipermeable wall. The polymers are known to theart in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and inHandbook of Common Polymers by Scott, J. R. and Roff, W. J., 1971,published by CRC Press, Cleveland, Ohio.

The laminated wall comprising a semipermeable lamina and a microporouslamina are in laminar arrangement and they act in concert to form anintegral laminated wall, that maintains its physical and chemicalintegrity and does not separate into lamina throughout the operativeagent release history of an osmotic device. The semipermeable lamina ismade from the semipermeable polymeric materials presented above, thesemipermeable homopolymers, the semipermeable copolymers, and the like.

Microporous lamina suitable for manufacturing an osmotic devicegenerally comprises preformed microporous polymeric materials, andpolymeric materials that can form a microporous lamina in theenvironment of use. The microporous materials in both embodiments arelaminated to form the laminated wall. The preformed materials suitablefor forming the microporous lamina are essentially inert, they maintaintheir physical and chemical integrity during the period of agent releaseand they can be generically described as having a sponge-like appearancethat provides a supporting structure for a semipermeable lamina and alsoprovide a supporting structure for microscopic-sized interconnectedpores or voids. The materials can be isotropic wherein the structure ishomogenous throughout a cross-sectional area, or they can be anisotropicwherein the structure is non-homogenous throughout a cross-sectionalarea. The pores can be continuous pores that have an opening on bothfaces of a microporous lamina, pores interconnected through tortuouspaths of regular and irregular shapes including curved, curved-linear,randomly oriented continuous pores, hindered connected pores and otherporous paths discernible by microscopic examination. Generally,microporous lamina are defined by the pore size, the number of pores,the tortuosity of the microporous path and the porosity which relates tothe size and the number of pores. The pore size of a microporous laminais easily ascertained by measuring the observed pore diameter at thesurface of the material under the electron microscope. Generally,materials possessing from 5% to 95% pores and having a pore size of from10 angstroms to 100 micrometers can be used for making a microporouslamina. The pore size and other parameters characterizing themicroporous structure also can be obtained from flow measurements, wherea liquid flux, J, is produced by a pressure difference ΔP, across thelamina. The liquid flux through a lamina with pores of uniform radiusextended through the membrane and perpendicular to its surface with areaA given by the relation 1:

    J=(Nπ.sup.4 ΔP)/(8ηΔx)                  (1)

wherein J is the volume transported per unit time and lamina areacontaining N number of pores of radius r, η is the viscosity of theliquid, and ΔP is the pressure difference across the lamina withthickness Δx. For this type of lamina, the number of pores N can becalculated from relation 2, wherein ε is the porosity defined as theratio of void volume to total volume of the lamina: and A is thecross-sectional area of the lamina containing N pores.

    N=εx[A/(πr.sup.2)]                              (2)

The pore radius then is calculated from relation 3:

    r=8η[(JΔxτ)/(AΔpε)]            (3)

wherein J is the volume flux through the lamina per unit area producedby the pressure difference ΔP across the lamina, η, ε and Δx have themeaning defined above and τ is the tortuosity defined as the ratio ofthe diffusional path length in the lamina to the lamina thickness.Relations of the above type are discussed in Transport Phenomena InMembranes, by Lakshminatayanaiah, N, Chapter 6, 1969, published byAcademic Press, Inc., New York.

As discussed in this reference on page 336, in Table 6.13, the porosityof the lamina having pore radii r can be expressed relative to the sizeof the transported molecule having a radius a, and as the ratio ofmolecular radius to pore radius a/r decreases, the lamina becomes porouswith respect to this molecule. That is, when the ratio a/r is less than0.3, the lamina becomes substantially microporous as expressed by theosmotic reflection coefficient σ which decreases below 0.5. Microporouslamina with a reflection coefficient σ in the range of less than 1,usually from 0 to 0.5, and preferably less than 0.1 with respect to theactive agent are suitable for fabricating the system. The reflectioncoefficient is determined by shaping the material in the form of alamina and carrying out water flux measurements as a function ofhydrostatic pressure difference and as a function of the osmoticpressure difference caused by the active agent. The osmotic pressuredifference creates a hydrostatic volume flux, and the reflectioncoefficient is expressed by relation 4: ##EQU1## Properties ofmicroporous materials are described in Science, Vol. 170, pages 1302 to1305, 1970; Nature, Vol. 214, page 285, 1967; Polymer Engineering andScience, Vol. 11, pages 284-288, 1971; U.S. Pat. Nos. 3,567,809 and3,751,536; and in Industrial Processing With Membranes, by Lacey R. E.,and Loeb, Sidney, pages 131 to 134, 1972, published by Wiley,Interscience, New York.

Microporous materials having a preformed structure are commerciallyavailable and they can be made by art-known methods. The microporousmaterials can be made by etched nuclear tracking, by cooling a solutionof flowable polymer below the freezing point whereby solvent evaporatesfrom the solution in the form of crystals dispersed in the polymer andthen curing the polymer followed by removing the solvent crystals, bycold or hot stretching at low or high temperatures until pores areformed, by leaching from a polymer a soluble component by an appropriatesolvent, by ion exchange reaction, and by polyelectrolyte processes.Processes for preparing microporous materials are described in SyntheticPolymer Membranes, by R. E. Kesting, Chapters 4 and 5, 1971, publishedby McGraw Hill, Inc.; Chemical Reviews, Ultrafiltration, Vol. 18, pages373 to 455, 1934; Polymer Eng. and Sci., Vol. 11, No. 4, pages 284 to288, 1971; J. Appl. Poly. Sci., Vol. 15, pages 811 to 829, 1971; and inU.S. Pat. Nos. 3,565,259; 3,615,024; 3,751,536; 3,801,692; 3,852,224;and 3,849,528.

Microporous materials useful for making the lamina include microporouspolycarbonates comprised of linear polyesters of carbonic acid in whichcarbonate groups recur in the polymer chain, microporous materialsprepared by the phosgenation of a dihydroxyl aromatic such as bisphenola, microporous poly(vinylchloride), microporous polyamides such aspolyhexamethylene adipamide, microporous modacrylic copolymers includingthose formed from poly(vinylchloride) 60% and acrylonitrite,styrene-acrylic and its copolymers, porous polysulfones characterized bydiphenylene sulfone groups in a linear chain thereof, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolic polyesters, microporouspoly(saccharides), microporous poly(saccharides) having substituted andunsubstituted anhydroglucose units and preferably exhibiting anincreased permeability to the passage of water and biological fluidsthan semipermeable lamina, asymmetric porous polymers, cross-linkedolefin polymers, hydrophobic or hydrophilic microporous homopolymers,copolymers or interpolymers having a reduced bulk density, and materialsdescribed in U.S. Pat. Nos. 3,597,752; 3,643,178; 3,654,066; 3,709,774;3,718,532; 3,803,061; 3,852,224; 3,853,601; and 3,852,388, in BritishPat. No. 1,126,849, and in Chem. Abst., Vol. 71 4274F, 22572F, 22573F,1969.

Additional microporous materials include poly(urethanes), cross-linked,chain-extended poly(urethanes), microporous poly(urethanes) in U.S. Pat.No. 3,524,753, poly(imides), poly(benzimidazoles), collodion (cellulosenitrate with 11% nitrogen), regenerated proteins, semi-solidcross-linked poly(vinylpyrrolidone), microporous materials prepared bydiffusion of multivalent cations into polyelectrolyte sols as in U.S.Pat. No. 3,565,259, anisotropic permeable microporous materials ofionically associated polyelectrolytes, porous polymers formed by thecoprecipitation of a polycation and a polyanion as described in U.S.Pat. Nos. 3,276,589; 3,541,055; 3,541,066 and 3,546,142, derivatives ofpoly(styrene) such as poly(sodium styrenesulfonate) and poly(vinylbenzyltrimethylammonium chloride), the microporous materials disclosedin U.S. Pat. No. 3,615,024 and U.S. Pat. Nos. 3,646,178 and 3,852,224.

Further, the microporous forming material used for the purpose of theinvention, includes the embodiment wherein the microporous lamina isformed in situ, by a pore-former being removed by dissolving or leachingit to form the microporous lamina during the operation of the system.The pore-former can be a solid or a liquid. The term liquid, for thisinvention, embraces semi-solids and viscous fluids. The pore-formers canbe inorganic or organic. The pore-formers suitable for the inventioninclude pore-formers that can be extracted without any chemical changein the polymer. The pore-forming solids have a size of about 0.1 to 200microns and they include alkali metal salts such as sodium chloride,sodium bromide, potassium chloride, potassium sulfate, potassiumphosphate, sodium benzoate, sodium acetate, sodium citrate, potassiumnitrate and the like. The alkaline earth metal salts include calciumphosphate, calcium nitrate, and the like. The transition metal saltsinclude ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,manganese fluoride, manganese fluorosilicate, and the like. Thepore-formers include organic compounds such as polysaccharides. Thepolysaccharides include the sugars sucrose, glucose, fructose, mannitol,mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose,monosaccharides and disaccharides. Also, organic aliphatic and aromaticoils, including diols and polyols, as exemplified by polyhydricalcohols, poly(alkylene glycols), polyglycols, alkylene glycols,poly(α-ω)-alkylenediols esters or alkylene glycols and the like; watersoluble cellulosic polymers such as hydroxyloweralkyl cellulose,hydroxypropyl methylcellulose, methyl cellulose, methylethyl cellulose,hydroxyethyl cellulose and the like; water soluble polymers such aspolyvinylpyrrolidone, sodium carboxymethylcellulose and the like; andwater soluble drugs usually in the form of addition salts such asprocainamide hydrochloride, propoxyphene hydrochloride and the like. Thepore-formers are nontoxic, and on their removal from the lamina channelsare formed through the lamina. In a preferred embodiment, the non-toxicpore-forming agents are selected from the group consisting of inorganicand organic salts, carbohydrates, polyalkylene glycols,poly(α-ω)-alkylenediols, esters of alkylene glycols, glycols, and watersoluble cellulosic polymers, useful for forming a microporous lamina ina biological environment. Generally, for the purpose of this invention,when the polymer forming the lamina contains more than 40% by weight ofa pore-former, or a mixture of a pore-former and a drug, the polymer isa precursor microporous lamina that on removing the pore-former, or thepore-former and the drug, yields a lamina which is substantiallymicroporous; at concentrations less than this, the lamina behaves like asemipermeable lamina or membrane. In this latter embodiment thesemipermable lamina comprises 0.5 to 40% by weight of drug, or a mixtureof drug and pore-former of 0.5 to 40% by weight.

The materials useful for forming a lamina containing drug that isinstantly available for immediate therapy include water solublepolysaccharide gums such as carrageenan, fucoidan, gum ghatti,tragacanthin, arabinogalactan, pectin, xanthan, and the like;water-soluble salts of polysaccharide gums such as sodium alginate,sodium tragacanthin, sodium gum ghattate, and the like; water-solublehydroxyalkylcellulose wherein the alkyl member is straight or branchedof 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, and the like; synthetic water-solublecellulosebased lamina formers such as methyl cellulose and itshydroxyalkyl methylcellulose cellulose derivatives such as a memberselected from the group consisting of hydroxyethyl methylcellulose,hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, and thelike; and other cellulose polymers such as sodiumcarboxymethylcellulose. Other lamina forming materials that can be usedfor this purpose include polyvinyl-pyrrolidone, polyvinylalcohol,polyethylene oxide, a blend of gelatin and polyvinyl-pyrrolidone,gelatin, glucose, saccharides, and the like.

The expression passageway as used herein comprises means and methodssuitable for releasing the agent or drug from the osmotic system. Theexpression includes aperture, orifice, hole, or bore through thesemipermeable wall or the laminated wall. The passageway can be formedby mechanical drilling, laser drilling, or by eroding an erodibleelement, such as a gelatin plug, in the environment of use. A detaileddescription of osmotic passageways, and the maximum and minimumdimensions for a passageway are disclosed in U.S. Pat. Nos. 3,845,770and 3,916,899.

The osmotically effective compounds that can be used for the purpose ofthe invention include inorganic and organic compounds that exhibit anosmotic pressure gradient against an external fluid across thesemipermeable wall or the laminated wall. The osmotically effectivecompounds are known also as osmotically effective solutes, or osmagents.The compounds are used by mixing them with an agent or drug that haslimited solubility in the external fluid with the compounds forming asolution containing agent that is osmotically delivered from the system.The phrase "limited solubility" as used herein means the beneficialagent or drug has a solubility of about less than 1% by weight in theaqueous fluid present in the environment. The osmotic solutes are usedby homogenously or heterogenously mixing the solute with the agent ordrug, and in one manufacture charging them into the reservoir. Thesolutes attract fluid into the reservoir producing a solution of solutewhich is delivered from the system concomitantly transportingundissolved and dissolved beneficial agent to the exterior of thesystem. Osmotically effective solutes used for the former purposeinclude magnesium sulfate, magnesium chloride, sodium chloride, lithiumchloride, potassium sulfate, sodium sulfate, lithium sulfate, potassiumacid phosphate, calcium lactate, d-mannitol, urea, inositol, magnesiumsuccinate, tartaric acid, carbohydrates such as raffinose, sucrose,glucose, α-d-lactose monohydrate, and mixtures thereof.

The osmotic solute is initially present in excess and it can be anyphysical form such as particle, crystal, pellet, tablet, strip, film orgranule. The osmotic pressure of saturated solutions of variousosmotically effective compounds and for mixtures of compounds at 37° C.,in water, is listed in Table 1. In the table, the osmotic pressure π, isin atmospheres, ATM. The osmotic pressure is measured in a commerciallyavailable osmometer that measures the vapor pressure difference betweenpure water and the solution to be analyzed, and according to standardthermodynamic principles, the vapor pressure ratio is converted intoosmotic pressure difference. In Table 1, osmotic pressures of from 20ATM to 500 ATM are set forth; of course, the invention includes the useof lower osmotic pressures from zero, and higher osmotic pressures thanthose set forth by way of example in Table 1. The osmometer used for thepresent measurements is identified as Model 320B, Vapor PressureOsmometer, manufactured by the Hewlett Packard Co., Avandale, Penna.

    ______________________________________                                        COMPOUND OR          OSMOTIC PRESSURE                                         MIXTURE              ATM                                                      ______________________________________                                        Lactose-Fructose     500                                                      Dextrose-Fructose    450                                                      Sucrose-Fructose     430                                                      Mannitol-Fructose    415                                                      Sodium Chloride      356                                                      Fructose             355                                                      Lactose-Sucrose      250                                                      Potassium Chloride   245                                                      Lactose-Dextrose     225                                                      Mannitol-Dextrose    225                                                      Dextrose-Sucrose     190                                                      Mannitol-Sucrose     170                                                      Dextrose              82                                                      Potassium Sulfate     39                                                      Mannitol              38                                                      Sodium Phosphate Tribasic.12H.sub.2 O                                                               36                                                      Sodium Phosphate Dibasic.7H.sub.2 O                                                                 31                                                      Sodium Phosphate Dibasic.12H.sub.2 O                                                                31                                                      Sodium Phosphate Dibasic Anhydrous                                                                  29                                                      Sodium Phosphate Monobasic.H.sub.2 O                                                                28                                                      ______________________________________                                    

The expression "active agent" as used herein broadly includes anycompound, or mixture thereof, that can be delivered from the system toproduce a beneficial result. The agent can be soluble in fluid thatenters the reservoir and functions as an osmotically effective solute orit can have limited solubility in the fluid and be mixed with anosmotically effective soluble soluble in fluid that is delivered fromthe system. The active agent used herein includes also any compoundsthat can be delivered from the wall for immediate therapy. The activeand beneficial agents nclude pesticides, herbicides, germicides,biocides, algicides, rodenticides, fungicides, insecticides,antioxidants, plant growth promoters, plant growth inhibitors,preservatives, disinfectants, sterilization agents, catalysts, chemicalreactants, fermentation agents, foods, food supplements, nutrients,cosmetics, drugs, vitamins, sex sterilants, fertility inhibitors,fertility promotors, air purifiers, micro-organism attenuators, andother agents that benefit that environment of use.

In the specification and the accompanying claims, the term "drug"includes any physiologically or pharmacologically active substances thatproduce a localized or systemic effect or effects in animals, which termincludes mammals, humans and primates. The term also includes domestichousehold, sport or farm animals such as sheep, goats, cattle, horsesand pigs, for administering to laboratory animals such as mice, rats andguinea pigs, and to fishes, to avians, to reptiles and zoo animals. Theterm "physiologically" as used herein denotes the administration of drugto produce normal levels and functions. The term "pharmacologically"denotes variations in response to amounts of drug including therapeuticsas defined in Stedman's Medical Dictionary, 1966, published by Williams& Wilkins, Baltimore, Md. The phrase drug formulation as used hereinmeans the drug is in the compartment by itself, or the drug is in thecompartment mixed with an osmotic solute, binder, dye, mixtures thereof,and the like. The active drug that can be delivered includes inorganicand organic compounds without limitation, including drugs that act onthe peripheral nerves, adrenergic receptors, cholinergic receptors,nervous system, skeletal muscles, cardiovascular, smooth muscles, bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, immunological system, reproductivesystem, skeletal system, autocoid systems, alimentary and excretorysystems, inhibitory of autocoids and histamine systems. The active drugthat can be delivered for acting on these animal systems includesdepressants, hypnotics, sedatives, psychic energizers, tranquilizers,anticonvulsants, muscle relaxants, antiparkinson agents, analgesics,anti-inflammatory, local anesthetics, muscle contractants,anti-microbials, anti-malarials, hormonal agents, contraceptives,sympathomimetics, diuretics, anti-parasitics, neoplastics,hypoglycemics, ophthalmics, electrolytes, diagnostic agents andcardiovascular drugs.

Drugs that act on the central nervous system include hypnotics andsedatives, including pentobarbital sodium, phenobarbital, secobarbital,thiopental and mixtures thereof; heterocyclic hypnotics such asdioxopiperidines and glutarimides; hypnotics and sedatives such asamides and ureas, exemplified by diethylisovaleramide andα-bromoisovaleryl urea; hypnotic and sedative urethanes and disulfanes;psychic energizers such as isocoboxazid, nialamide, phenelzine,imipramine, tranylcypromine and parglyene; tranquilizers such aschloropromazine, promazine, fluphenazine, reserpine, deserpidine,meprobamate, and benezodiazepines such as chlordiazepoxide;anticonvulsants such as primidone, enitabas, diphenylhydantion,ethltion, pheneturide and ethosuximide; muscle relaxants andantiparkinson agents such as mephenesin, methocarbomal, trihexlphenidyl,and biperiden; anti-hypertensives such as methyl dopa andL-β-3-4-dihydroxypenhnylalanine, and pivaloyloxyethyl ester ofα-methyldopa hydrochloride dihydrate; analgesics such as morphine,codeine, meperidine, nalorphine, antipyretics and anti-inflammatoryagents such as aspirin, indomethacin, salicylamide, naproxen, colchicinefenoprofen, sulidac, diclofenac, indoprofen and sodium salicylamide,local anesthetics such as procaine, lidocaine, maepaine, piperocaine,tetracaine and dibucane; antispasmodics and muscle contractants such asatropine, scopolamine, methscopolamine, oxyphenonium, papaverine;prostaglandins such as PGE₁ PGE₂, PGF₁α, PGF₂α and PGA; anti-microbialssuch as penicillin, tetracycline, oxytetracycline, chlorotetracycline,chloramphenicol and sulfonamides; anti-malarials such as4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal agentssuch as prednisolone, cortisone, cortisol and triamcinolone; androgenicsteroids such as methyltesterone, and fluoxmesterone; estrogenicsteroids such as 17β-estradiol, α-estradiol, estriol, α-estradiol3-benzoate, and 17-ethynyl estradiol-3-methyl ether; progestationalsteroids such as progesterone, 19-nor-pregn-4-ene-3,20-dione,17-hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one,17α-ethynyl-17-hydroxy-5(10)-estren-3-one, and 9β,10α-pregna-4,6-diene-3,20-dione; sympathomimetic drugs such as epinephrine, amphetamine,ephedrine and norepinephrine; hypotensive drugs such as hydralazine,cardiovascular drugs such as procainamide, procainamide hydrochloride,amyl nitrite, nitroglycerin, dipyredamole, sodium nitrate and mannitolnitrate; diuretics such as chlorathiazide, acetazolamide, methazolamideand flumethiazide; antiparasitics such as bephenium, hydroxynaphthoate,dichlorophen and dapsone; and neoplastics such as nechlorethamine,uracil mustard, 5-fluorouracil, 6-6-thioguanine and procarbazine;β-blockers such as pindolol, propranolol, practolol, metoprolol,oxprenolol, timolol, atenolol, alprenolol, and acebutolol; hypoglycemicdrugs such as insulin, isophane insulin, protamine zinc insulinsuspension, globin zinc insulin, extended insulin zinc suspension,toblutamide, acetohexamide, tolazamide and chlorpropamide; antiulcerdrugs such as cimetidine; nutritional agents such as ascorbic acid,niacin, nicotinamide, folic acid, choline, biotin, pantothenic acid, andvitamin B₁₂ ; essential amino acids; essential fats; eye drugs such aspilocarpine, pilocarpine salts such as pilocarpine nitrate, pilocarpinehydrochloride, dichlophenamide, atropine, atropine sulfate, scopolamineand eserine salicylate; histamine receptor antagonists such ascimetidine; and electrolytes such as calcium gluconate, calcium lactate,potassium chloride, potassium sulfate, sodium chloride, potassiumfluoride, sodium fluoride, ferrous lactate, ferrous gluconate, ferroussulfate, ferrous fumurate and sodium lactate; and drugs that act onα-adrenergic receptors such as clonidine hydrochloride. The beneficialdrugs are known to the art in Remington's Pharmaceutical Sciences, 14thEd., 1970, published by Mack Publishing Co., Easton, Penna.; and in ThePharmacological Basis of Therapeutics, by Goodman and Gilman, 4th Ed.,1970, published by The MacMillan Company, London.

The drug can be in various forms, such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as hydrochlorides,hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrite,nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate. Foracid drugs, salts of metals, amines or organic cations, for examplequaternary ammonium can be used. Derivatives of drugs such as esters,ethers and amides which have solubility characteristics suitable for useherein can be used alone or mixed with other drugs. Also, a drug that iswater insoluble can be used in a form that is a water soluble derivativethereof to effectively serve as a solute, and on its release from thedevice, is converted by enzymes, hydrolyzed by body pH or othermetabolic processes to the original form, or to a biologically activeform. The agent can be in the reservoir compartment as a dispersion,paste, cream, particle, granule, emulsion, suspension or powder. Also,the agent can be mixed with a binder, dispersant, emulsifier or wettingagent, lubricant, and dyes.

The amount of agent present in the system is initially in excess of theamount that can be dissolved in the fluid that enters the reservoir.Under this physical state when the agent is in excess, the system willosmotically operate to give a substantially constant rate of release.The rate of release can also be varied by having different amounts ofagent in the reservoir to form solutions containing differentconcentrations of agent for delivery from the device. Generally, thesystem can house from 0.05 ng to 5 grams or more, with individualsystems containing for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500mg, 750 mg, 1.5 g, and the like. The amount of drug in a semipermeablewall usually is 0.5 ng up to 50 mg, in a microporous lamina usuallyabout 0.5 mg up to 85 mg, and the amount in a water soluble lamina isabout 0.5 ng up to 85 mg. The osmotic device can be administered once,twice or thrice daily.

The solubility of an agent in the fluid can be determined by knowntechniques. One method consists of preparing a saturated solutioncomprising the fluid plus the agent as ascertained by analyzing theamount of agent present in a definite quantity of the fluid. A simpleapparatus for this purpose consists of a test tube of medium sizefastened upright in a water bath maintained at constant temperature andpressure, in which the fluid and agent are placed and stirred by arotating glass spiral. After a given period of stirring, a weight of thefluid is analyzed and the stirring continued an additional period oftime. If the analysis shows no increase of dissolved agent aftersuccessive periods of stirring, in the presence of excess solid agent inthe fluid, the solution is saturated and the results are taken as thesolubility of the product in the fluid. If the agent is soluble, anadded osmotically effective compound optionally may not be needed; ifthe agent has limited solubility in the fluid, then an osmoticallyeffective compound can be incorporated into the device. Numerous othermethods are available for the determination of the solubility of anagent in a fluid. Typical methods used for the measurement of solubilityare chemical and electrical conductivity. Details of various methods fordetermining solubilities are described in United States Public HealthService Bulletin, No. 67 of the Hygenic Laboratory; Encyclopedia ofSchience and Technology, Vol. 12, pages 542 to 556, 1971, published byMcGraw-Hill, Inc.; and Encyclopedia Dictionary of Physics, Vol. 6, pages547 to 557, 1962, published by Pergamon Press, Inc.

The systems of the invention are manufactured by standard techniques.For example, in one embodiment, the agent and other ingredients that maybe housed in the compartment and a solvent are mixed into a solid,semisolid or gel form by conventional methods such as ballmilling,calendering, stirring, or rollmilling and then pressed into apreselected shape. The laminae forming the system can be applied bymolding, spraying or dipping the pressed shape into wall formingmaterials. In another embodiment, the laminae can be cast into films,shaped to the desired dimensions, an exterior lamina sealed to aninterior lamina to define a compartment that is filled with agent andthen closed. The system also can be manufactured with an emptycompartment that is filled through the passageway. The system, whenformed of more than one laminate, is joined by various joiningtechniques, such as high frequency electronic sealing that providesclean edges and a firmly sealed system. Another, and presently preferredtechnique that can be used to apply laminate to a compartment is the airsuspension procedure. This procedure consists in suspending and tumblingthe pressed agent in a current of air and a lamina composition until thelamina is applied to the agent. The procedure is repeated with adifferent lamina to form the laminate. The air suspension procedure isdescribed in U.S. Pat. No. 2,799,241; J Am. Pharm. Assoc., Vol. 48,pages 451 to 459, 1979; and ibid, Vol. 49, pages 82 to 84, 1960. Otherstandard manufacturing procedures are described in Modern PlasticsEncyclopedia, Vol. 46, pages 62 to 70, 1969; and in PharmaceuticalSciences, by Remington, 14th Edition, pages 1626 to 1678, 1970,published by Mack Publishing Co., Easton, Penna.

Exemplary solvent suitable for manufacturing the laminates and laminaeinclude inert inorganic and organic solvents that do not adversely harmthe materials and the final laminated wall. The solvents broadly includemembers selected from the group consisting of aqueous solvents,alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenatedsolvents, cycloaliphatic, aromatics, heterocyclic solvents and mixturesthereof. Typical solvents include acetone, diacetone alcohol, methanol,ethanol, isopropyl alcohol, butyl alcohol, methyl acetate ethyl acetate,isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methylpropyl keton, n-hexane, n-heptane, ethylene glycol monoethyl ether,ethylene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, carbon tetrachloride, nitroethane,nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,cyclohexane, cyclooctane, benezene, toluene, naphtha, 1,4-dioxane,tetrahydrofuran, diglyme, water, and mixtures thereof such as acetoneand water, acetone and methanol, acetone and ethyl alcohol, methylenedichloride and methanol, and ethylene dichloride and methanol.

DETAILED DESCRIPTION OF EXAMPLES

The following examples are merely illustrative of the present invention,and they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

An osmotic delivery system manufactured as an osmotic device shaped,sized and adapted as an osmotic tablet for oral admittance into thegastrointestional tract is manufactured as follows: first, 53 g ofsodium indomethacin trihydrate is blended with 47 g of mannitol and 33 gof water into a homogenous blend. The ingredients are blended in a smalllaboratory blender for 30 minutes, and then the blend is passed througha 20 mesh screen. Next, the screened, homogenous blend is dried in anoven at 50° C. for about 2 hours, removed from the oven and passedthrough a 10 mesh screen. The latter screened granules are returned tothe oven and dried at 50° C. for an additional 2 hours. Next, the driedgranulation is mixed with 2% by weight of magnesium stearate and pressedinto a number of drug cores with a standard tablet machine. Thecompressed drug cores each have a diameter of about 6.5 mm and weight of190 mg. The drug cores are next coated with a semipermeable wall-formingcomposition containing sodium indomethacin trihydrate. The compositioncomprises 13 g of sodium indomethacin trihydrate and 117 g of celluloseacetate having an acetyl content of 32%. The wall is formed from asolvent system comprising 260 ml of water and 2900 ml of acetone. AWurster air suspension coater is used to form the semipermeable wallcontaining the anti-inflammatory drug. The solvent is evaporated in acirculating air oven at 50° C. for 65 hours, and after cooling to roomtemperature a 0.25 mm diameter passageway is laser drilled through thesemipermeable wall. The passageway connects the exterior of the osmoticdevice with the drug compartment for releasing drug. The final osmoticdevice contained 52% sodium indomethacin trihydrate, 46% mannitol and 2%magnesium stearate in the compartment and the semipermeable wallconsists of 90% of cellulose acetate having an acetyl content of 32%,and 10% sodium indomethacin trihydrate. The percents are weight percent.

EXAMPLE 2

A series of osmotic devices manufactured as oral osmotic tablets aremade for demonstrating the release of drug from a semipermeable wallsurrounding a compartment as follows: first, 3500 g of potassiumchloride is mixed in a blender with 17.5 g of silicon dioxide and 1.75 gof magnesium stearate for about 30 minutes. The blending is carried outat room temperature. Next, the blend is converted to 11 mm diameter drugcores by charging the blend into the cavities of a tablet press, and acompression force of 1 ton applied across a punch to compress the drug.The drug cores next are coated with a composition comprising celluloseacetate having an acetyl content of 32% and sodium indomethacintrihydrate. The semipermeable wall formed consists of 88.5% celluloseacetate having an acetyl content of 32% and 11.5% sodium indomethacintrihydrate. The semipermeable wall is 0.3 mm thick and a 0.25 mmdiameter passageway is laser drilled through the semipermeable wall. Therelease rate in water in mg/hr of sodium indomethacin from thesemipermeable wall measured by UV absorbance is seen in FIG. 9.

EXAMPLE 3

An osmotic, therapeutic device for the instant release and thecontrolled and continuous release for oral administration of abeneficial appetite suppressant is manufactured as follows: first,2,284.8 g of the sympathomimetric, anorectic drug phenylpropanolaminehydrochloride is passed through a number 30 mesh screen and transferredto a blending bowl. Next, 91.2 g of hydroxypropyl methylcellulose isadded to 510 ml of ethanol-water system 84:16 by volume in a separateblender and blended until a clear solution is produced. Then, thehydroxypropyl methylcellulose-ethanol-water solution is added to thephenylpropanolamine hydrochloride and blended for 1 hour to produce aneven consistency. Next, the wet granulation is passed through a number30 stainless steel mesh screen, the granules spread on a tray, and driedin a forced air oven at 50° C.±2° C. The granules are dried for 20 to 25hours, and after cooling to room temperature of 22.2° C. the driedgranules are passed through a number 20 stainless steel sieve. Thegranulation is returned to the blending bowl and 24 g of stearic acid,previously passed through a number 80 stainless steel sieve, is added tothe bowl and all the ingredients blended on low speed for 10 minutes.Finally, a number of drug formulations, which became the drug reservoirsof the osmotic device, are made by compressing the drug formulationcontaining all the ingredients in a 6 mm die cavity under a compressionload of 900 kg. The final drug formulation consists essentially of 55 mgof phenylpropanolamine hydrochloride, 2.5 mg of hydroxypropylmethylcellulose and 0.6 mg of stearic acid.

Next, a semipermeable wall is formed around the drug cores by blending150 g of cellulose acetate having an acetyl content of 39.8% with 2493ml of methylene chloride and 456 ml of methanol and spray coating thesemipermeable wall forming composition around the drug cores in aconventional air suspension coater. The wall forming coating iscontinued until all the coating solution is used, usually over a periodof 1 to 2 hours. Then, a second laminate forming composition comprising352 g of dry phenylpropanolamine hydrochloride and 88 g of dryhydroxypropyl methylcellulose in a solvent system comprising 2842 ml ofmethylene chloride and 2578 ml of methanol is prepared by adding thedrug ingredients to the solvent system with continual mixing for 30minutes to produce a clear laminate forming solution. The solution isadded to the air suspension coater and a laminate is coated onto thesemipermeable wall. Finally, the coated osmotic devices are placed onstainless steel trays and dried at 50° C. for 48 hours, and then anosmotic passageway is laser drilled through the laminated wall. Theosmotic passageway has a diameter of about 0.25 mm. FIG. 10 depicts therelease rate profile for osmotic devices provided according to thisexample. The osmotic devices provide first a therapeutically effectiveinitial pulse dose of drug over a short delivery period accompanied by atherapeutically effective amount of drug delivered at a controlled rateand continuously over a prolonged period of time. FIG. 11 depicts alaminated structure made according to the example. The laminate alsocould be made by solvent casting of the laminae. The laminate comprisesa semipermeable lamina 37 formed of a cellulose acylate that maintainsits physical integrity in aqueous and biological environments, whichlamina 37 is in laminar arrangement with a lamina 38 formed of amaterial that looses its physical integrity in an aqueous or biologicalenvironment. Lamina 38 contains drug 39 that is released from lamina 38as it changes its integrity.

EXAMPLE 4

A therapeutic, osmotic device, adapted and shaped as an osmotic tabletfor administering orally a therapeutically effective amount of thehistamine H₂ receptor antagonist cimetidine hydrochloride for themanagement of daytime and nocturnal basal gastric acid secretion and itsaccompanying ulcers is manufactured as follows: a multiplicity ofdrugforming reservoirs each containing 740 mg of cimetidinehydrochloride, 32 mg of polyvinyl pyrrolidone, 16 mg of cross-linkedsodium carboxymethylcellulose and 8 mg of magnesium stearate are formedby first blending the polyvinyl pyrrolidone with an ethanol-watersolvent, 70-30, vol-vol, for about 15-20 minutes to produce a solution.Separately, the sodium carboxymethylcellulose and the cimetidinehydrochloride are blended, passed through a number 40 mesh sieve. Thenthe polyvinyl pyrrolidone solution is added in small increments to thecarboxymethylcellulose-cimetidine homogenous blend in a blender bowl,and all the ingredients blended for 20-25 minutes to produce a blendhaving the consistency of wet paste. The wet paste is passed through anumber 10 sieve and the screened granules dried for 24 hours at 50° C.The dried granules are passed through a 20 mesh screen, and themagnesium stearate mixed therewith. The blending is continued for 5 to10 minutes, and the final blend fed to a die and punched into drugforming reservoir cores, having an elliptical shape measuring 3/4inches, 20 mm, across its longest axis.

Next a semipermeable wall is formed around the drug cores by coating thedrug cores with a semipermeable wall forming composition comprising: inpercent by weight: 29.2% cellulose acetate having an acetyl content of32%; 30.8% cellulose acetate having an acetyl content of 39.8%; 20%cimetidine hydrochloride; 14% hydroxypropyl methylcellulose; and, 6%polyethylene glycol 4000, in an 80% methylene chloride20% methanolsolvent system. The drug cores are coated in an air suspension machineuntil all the coating solution is used, requiring usually 1 to 2 hours.The final semipermeable wall surrounding the drug core weighed about 50mgs, and was about 0.12 mm thick. A 0.26 mm exit port is laser drilledthrough the semipermeable wall. In operation in a fluid environment, theosmotic device delivers drug from the wall and from the drug reservoirthrough the exit port to a biological drug receptor.

EXAMPLE 5

The procedure of Example 4 is repeated with the device made asdescribed, and in this example an outermost lamina is laminated onto thesemipermeable wall. The outermost lamina is water soluble and itcomprises 80% cimetidine hydrochloride monohydrate and 20% hydroxypropylmethylcellulose. The lamina is laminated onto the semipermeable wall inan air suspension coating machine with a methylene chloride-methanolsolvent, in a 75% to 25% vol to vol ratio. An osmotic exit port is laserdrilled through the laminated wall. In operation, in a fluidenvironment, the outermost water soluble wall instantly delivers a pulseamount of drug, followed by drug delivered from the semipermeable walland from the drug reservoir through the osmotic port. FIG. 12 depictsthe laminated wall provided by this example. The laminate comprises asemipermeable lamina 40 in laminar arrangement with a water solublelamina 41. Lamina 40 is formed of a member selected from the groupconsisting of cellulose acylate, cellulose diacylate and cellulosetriacylate having drug 42 dispersed therein, and lamina 41 is formed ofa water soluble member selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, polyvinyl-pyrrolidone andpolyvinylalcohol containing drug 43. The laminate also can be made bysuccessive casting of the laminae.

EXAMPLES 6-7

The procedure of Examples 4 and 5 are repeated in this example. Theosmotic devices produced by this example comprised of drug coreconsisting essentially of 94% cimetidine hydrochloride monohydrate, 4%polyvinylpyrrolidone and 2% magnesium stearate; a microporous laminaadjacent to and surrounding the reservoir, comprising 45% celluloseacetate having an acetyl content of 39.8%, 27.5% polyethylene glycol4000, and 27.5% hydroxypropylmethylcellulose; and a semipermeable laminadistant from the drug and in laminar arrangement with the microporouslamina, the semipermeable lamina comprising 29.8% cellulose acetatehaving an acetyl content of 32%, 10.2% cellulose acetate having anacetyl content of 39.8%, and 20% hydroxypropyl methylcellulose. Thediameter of the passageway is 0.26 mm. FIG. 13 depicts the release ratefrom this device and FIG. 14 depicts the cumulative amount released overtime from the same device.

An osmotic device comprising drug in its outer lamina is prepared asdescribed with the device consisting essentially of the following: adrug core consisting essentially of 94% cimetidine hydrochloridemonohydrate, 4% polyvinylpyrrolidone, and 2% magnesium stearate; amicroporous lamina adjacent to and surrounding the reservoir comprising45% cellulose acetate having an acetyl content of 39.8%, 27.5%hydroxypropyl methylcellulose, and 27.5% polyethylene glycol 4000; and asemipermeable lamina distant from the drug reservoir consistingessentially of 69.8% cellulose acetate having an acetyl content of 32%,10.2% cellulose acetate having an acetyl content of 39.8% and 20%cimetidine hydrochloride monohydrate. The diameter of the passageway is0.26 mm. FIG. 15 depicts the pulse release of drug from the lamina andthe release rate through the passageway from the device. FIG. 16 depictsthe cumulative amount released from the lamina and the drug reservoirthrough the passageway over time.

EXAMPLE 8

The procedure of Examples 4 and 5 are followed in this example formanufacturing an osmotic device having a drug reservoir weighing 720 mg.The drug reservoir comprised 94% cimetidine hydrochloride monohydrate,4% polyvinylpyrrolidone, and 2% magnesium stearate. The semipermeablewall surrounding the drug reservoir comprised 78.5% cellulose acetatehaving an acetyl content of 32%, 11.5% cellulose acetate having anacetyl content of 39.8% and 10% cimetidine hydrochloride monohydrate.The semipermeable wall was 2 mil (0.05 mm) thick and the diameter of thepassageway was 0.26 mm. The device delivered 45 mg of cimetidine duringthe first hour, including 2 mg from the wall and it had an averagedelivery rate of about 35 mg of cimetidine per hour over a prolongedperiod of 12 hours.

EXAMPLE 9

The procedure of Examples 4 and 5 are followed in this example, formanufacturing an oral osmotic device having a drug reservoir weighing776 mg. The drug reservoir comprised 94% cimetidine hydrochloridemonohydrate present as 77.3% cimetidine and 16.7% hydrochloridemonohydrate, 4% polyvinylpyrrolidone and 2% magnesium stearate. The wallsurrounding the reservoir comprised an inner semipermeable laminaconsisting of 69.8% cellulose acetate having an acetyl content of 32%,10.2% cellulose acetate having an acetyl content of 39.8%, and 20%hydroxypropyl methylcellulose in laminar arrangement with an outermicroporous wall consisting essentially of 28% cellulose acetate havingan acetyl content of 39.8%, 2% hydroxypropylmethylcellulose, and 70%cimetidine hydrochloride monohydrate. The diameter of the passageway was0.26 mm, the semipermeable wall was 0.04 mm thick, and the microporouswall was 0.24 mm thick. The release rate profile is illustrated in FIG.17. In FIG. 18, a laminate is depicted comprising semipermeable lamina44, and microporous lamina 45 containing drug 46.

EXAMPLE 10

The procedure of Examples 4 and 5 are followed for producing an osmoticdevice comprising a drug reservoir weighing 946 mg and consistingessentially of 94% cimetidine hydrochloride monohydrate, 4%polyvinylpyrrolidone, and 2% magnesium stearate; an inner semipermeablelamina consisting essentially of 69.8% cellulose acetate having anacetyl content of 32%, 10.2% cellulose acetate having an acetyl contentof 39.8% and 20% hydroxypropyl methylcellulose; a middle microporouslamina consisting essentially of 45% cellulose acetate having an acetylcontent of 39.8% and 55% cimetidine hydrochloride monohydrate; and anouter water dissolvable lamina consisting essentially of 80% cimetidinehydrochloride monohydrate and 20% hydroxypropyl methylcellulose. Thediameter of the passageway was 0.26 mm. The release rate for the deviceis illustrated in FIG. 19. The laminate provided by the invention isseen in FIG. 20, comprising semipermeable lamina 47, microporous lamina48 and water dissolvable lamina 49. Lamina 48 and lamina 49 containinstant releasable drug 50. FIG. 21 illustrates a laminate comprising asemipermeable lamina 51, microporous lamina 52 and water dissolvablelamina 53 containing drug 54.

EXAMPLE 11

The above procedures are repeated with all procedures as describedexcept that drug reservoir and the lamina contain ranitidinehydrochloride.

The present invention provides many advantages to the medical andveterinary art as described in detail above. The present invention alsoprovides a method for lessening the loss of drug in an animal needingthe drug by providing an initial burst of drug for diminishing the lossof drug arising from the transit of drug in the gastrointestional tractand for diminishing the loss of drug arising from metabolism of drug inthe liver. Concomitantly, the present invention provides a method forincreasing the therapeutically effective amount of drug available forproducing a physiological or pharmacological bioaffecting result in ananimal by providing drug for lessening in vivo loss, commonly attributedto first-pass effect, while simultaneously providing drug for producingthe intended drug result in management of health and disease. Obviously,many modifications and variations of the instant invention are possiblein the light of the above teachings. It is therefore to be understoodthat within the scope of the disclosure and appended claims, theinvention may be practiced otherwise than is described specificallyherein.

We claim:
 1. An osmotic device for delivering a beneficial agent to anenvironment of use, the osmotic device comprising:(a) a wall at least inpart formed of a substantially inert material which surrounds and formsa compartment containing a beneficial agent formulation, saidsubstantially inert material being permeable to the passage of anexterior fluid present in the environment of use and substantiallyimpermeable to the passage of the beneficial agent in the compartment;(b) a beneficial agent in the wall, said agent being released from thewall when the osmotic device is in operation in a fluid environment ofuse; and, (c) an osmotic passageway in the wall communicating with thecompartment and the exterior of the device for dispensing the beneficialagent from the compartment when the device is in the environment of usewherein fluid passes through the wall, causes the formation of anosmotic pressure gradient across the wall and dispenses the beneficialagent from the compartment to the environment via the osmoticpassageway.
 2. The osmotic device for delivering the beneficial agentaccording to claim 1, wherein the wall is formed of a semipermeablematerial containing the beneficial agent that is released therefrom in apulsed amount.
 3. The osmotic device for delivering the beneficial agentaccording to claim 1, wherein the wall is a laminate that surrounds thecompartment and comprises a semipermeable lamina adjacent to thecompartment, and a microporous lamina in laminar arrangement with thesemipermeable lamina and distant from the compartment, which microporouslamina contains a beneficial agent that is released therefrom in pulsedamount.
 4. The osmotic device for delivering the beneficial agentaccording to claim 1, wherein the wall is a laminate that surrounds thecompartment and comprises a semipermeable lamina adjacent to thecompartment, and a water soluble lamina in laminar arrangement with thesemipermeable lamina distant from the compartment, which water solublelamina contains a beneficial agent that is released therefrom in apulsed amount.
 5. The osmotic device for delivering the beneficial agentaccording to claim 1, wherein the wall is a laminate that surrounds thecompartment and comprises a semipermeable lamina adjacent to thecompartment containing a beneficial agent that is released therefrom ina pulsed amount, and a water soluble lamina in laminar arrangementdistant from the compartment that contains a beneficial agent that isreleased therefrom in a pulsed amount.
 6. The osmotic device fordelivering the beneficial agent according to claim 1, wherein thebeneficial agent is released from the wall in a short period of time andfrom the compartment over a prolonged period of time.
 7. The osmoticdevice for delivering the beneficial agent according to claim 1, whereinthe wall is a laminate that surrounds the compartment and comprises aninner semipermeable lamina, a middle microporous lamina, and an outerwater soluble lamina containing beneficial agent that is releasedtherefrom in a short period of time.
 8. The osmotic device fordelivering the beneficial agent according to claim 1, wherein the wallis a laminate that surrounds the compartment and comprises an innerlamina formed of a semipermeable material, a middle lamina formed of amicroporous material containing a beneficial agent that is releasedtherefrom in a short period of time, and an outer lamina formed of awater soluble material containing a beneficial agent that is releasedtherefrom in a short period of time.
 9. The osmotic device fordelivering the beneficial agent according to claim 7, wherein thebeneficial agent is released from the outer lamina in a short pulsedperiod of time followed by the beneficial agent released from the middlelamina.
 10. The osmotic device for delivering the beneficial agentaccording to claim 1, wherein the beneficial agent is released from thewall concomitantly with beneficial agent being delivered through thepassageway from the device.
 11. The osmotic device for delivering thebeneficial agent according to claim 1, wherein the beneficial agent isreleased from the wall followed by delivery through the osmoticpassageway from the device.
 12. An osmotic device for the controlleddelivery of a beneficial drug to a biological environment of use, theosmotic device comprising:(a) a shaped wall at least in part formed of asubstantially inert semipermeable material, which surrounds and forms acompartment containing a drug formulation, said substantially inertmaterial being permeable to the passage of a fluid present in theenvironment of use, and substantially impermeable to the passage of thedrug in the compartment; (b) a beneficial drug carried by the shapedwall that is released therefrom when the device is in operation in theenvironment of use,; (c) the drug formulation in the compartmentexhibiting an osmotic pressure gradient across the shaped wall against afluid present in the environment of use, said drug formulationcomprising a dosage amount of drug; and, (c) a passageway in the wallconnecting the compartment with the exterior of the osmotic device fordelivering drug formulation from the compartment to the environment ofuse wherein fluid passes through the wall, causes the formation of anosmotic pressure gradient across the wall and dispenses the drug fromthe compartment to the environment via the passageway.
 13. The osmoticdevice for delivering the beneficial agent according to claim 12,wherein the compartment contains an osmagent.
 14. The osmotic device forthe controlled delivery of the beneficial drug according to claim 12,wherein the wall is at least in part formed of a semipermeable materialthat is a member selected from the group consisting of celluloseacylate, cellulose diacylate, cellulose triacylate, cellulose acetate,cellulose diacetate, and cellulose triacetate.
 15. The osmotic devicefor the controlled delivery of the beneficial drug according to claim12, wherein the beneficial drug is cimetidine.
 16. The osmotic devicefor the controlled delivery of the beneficial drug according to claim12, wherein the beneficial drug is ranitidine.
 17. The osmotic devicefor the controlled delivery of the beneficial drug according to claim12, wherein the beneficial drug is phenylpropanolamine.
 18. The osmoticdevice for the controlled delivery of the beneficial drug according toclaim 12, wherein the environment of use is the gastrointestional tract.19. The osmotic device for the controlled delivery of the beneficialdrug according to claim 12, wherein the environment of use is a human.20. The osmotic device for the controlled delivery of the beneficialdrug according to claim 12, wherein the device is adapted and sized fororal use in a warm-blooded animal, and when in operation, the devicereleased drug from the wall and imbibed fluid through the wall into thecompartment in a tendency towards osmotic equilibrium at a ratecontrolled by the wall and the osmotic pressure gradient across the wallproducing a drug formulation solution that is dispensed from the deviceat a controlled rate and continuously over a prolonged period of time.21. The osmotic device for delivering a beneficial drug to theenvironment of use according to claim 12, wherein the drug is releasedin a short period of time from the wall for providing beneficial druginstantly to the environment of use.
 22. The osmotic device for thecontrolled delivery of a beneficial drug to the biological environmentof use according to claim 12, wherein the drug in the wall is the sameas the drug in the compartment.
 23. The osmotic device for thecontrolled delivery of a beneficial drug to the biological environmentof use according to claim 12, wherein the drug in the wall is differentthan the drug in the compartment.
 24. The osmotic device for thecontrolled delivery of a beneficial drug to the biological environmentof use according to claim 12, wherein the wall is formed in part of thesemipermeable material with the remainder of the wall formed of animpermeable material.
 25. The osmotic device for the controlled deliveryof a beneficial drug to the biological environment of use according toclaim 12, wherein the wall releases the drug in a pulsed therapeuticallyeffective amount.
 26. The osmotic device for the controlled delivery ofa beneficial drug to the biological environment of use according toclaim 12, wherein the device delivers drug from the compartment in atherapeutically effective amount over a prolonged period of time. 27.The osmotic device for the controlled delivery of a beneficial drug tothe biological environment of use according to claim 12, wherein theshaped wall is a laminate comprising a semipermeable lamina and amicroporous lamina.
 28. The osmotic device for the controlled deliveryof a beneficial drug to the biological environment of use according toclaim 12, wherein the shaped wall comprises a lamina that contains thedrug.
 29. The osmotic device for delivering the beneficial agentaccording to claim 1, wherein the beneficial agent in the compartment isthe same as the beneficial agent in the wall.
 30. The osmotic device fordelivering the beneficial agent according to claim 1, wherein thebeneficial agent in the compartment is different than the beneficialagent in the wall.
 31. The osmotic device for delivering the beneficialagent according to claim 1, wherein the beneficial agent formulation inthe compartment exhibits an osmotic pressure gradient across the wallagainst a fluid present in the environment of use.
 32. The osmoticdevice for delivering a beneficial drug to the environment of useaccording to claim 12, wherein the beneficial drug carried by the shapedwall is carried by a water soluble lamina.
 33. The osmotic device fordelivering a beneficial drug to the environment of use according toclaim 12, wherein the shaped wall is a laminate and the beneficial drugis carried by a lamina coated onto the shaped wall.
 34. The osmoticdevice for delivering a beneficial drug to the environment of useaccording to claim 12, wherein the shaped wall is a laminate comprisinga semipermeable lamina and a microporous lamina, and the beneficial drugis carried by the microporous lamina.